1. Description of the Prior Art
The substituted phenylthioamidine compounds of the invention can be prepared by procedures analogous to known methods. Typical methods which can be employed include the reaction of an arylthioacetonitrile with hydroxylamine hydrochloride in the procedure similar to that of Bruderlein, U.S. Pat. No. 3,334,137, or the reaction of a phenylthioacetonitrile with methanol in the presence of sodium methylate, followed by reaction with ammonium chloride, in a procedure analogous to that of Schaefer and Peters, J. Org. Chem. 26, 412 (1961).
2. Summary of the Invention
This invention is directed to substituted arylthioamidine compounds and is particularly directed to substituted phenylthioacetamidine compounds and their pharmaceutically-acceptable salts, the compounds corresponding to the formula: ##SPC1##
Wherein R represents tertiary butyl (tert-butyl) or halo and X represents hydrogen or hydroxyl. The compounds of the invention are solids or viscous liquids at ordinary temperatures, and are variously soluble in conventional solvents such as water, alcohols, ether, benzene, chlorinated hydrocarbons and the like. The free base compounds are generally less soluble in water than the salts, particularly under alkaline conditions, while the pharmaceutically-acceptable salts are generally of moderate to good solubility in water and alcohols.
In the present specification, the term halo is employed to designate one of the halogen moieties, fluoro, chloro, bromo or iodo. The compounds of the invention wherein X is hydroxyl are named as acetamidoximes. For convenience, both the acetamidines and corresponding oximes can be referred to generically as substituted amidines. The term pharmaceutically-acceptable salt as herein employed refers to salts of a substituted amidine which are substantially non-toxic at dosages consistent with good pharmacological activity. Such pharmaceutically-acceptable salts include non-toxic acid addition salts with inorganic acids such as hydrochloric, hydrobromic, sulfuric or phosphoric acid, or with organic acids such as acetic, succinic, malic, maleic, tartaric or citric acid, or with organic sulfonic acids such as methane-sulfonic or p-toluenesulfonic acid.
The substituted amidines of the invention have been found to be useful for administration to laboratory animals in the study of drug effects on the cardiovascular system, and have been found to be particularly useful in inhibiting aggregation of blood platelets. The compounds wherein R is halo are highly active against bacterial organisms commonly involved in infections of the urinary tract, and can be administered orally to animals to impart antimicrobial activity to the urine in combatting microorganisms such as Ps. aeruginosa, E. coli and Proteus vulgaris, organisms commonly involved in urinary tract infections.
The substituted amidines of the invention are prepared by the reaction of the corresponding substituted phenylthioacetonitrile with hydroxylamine in aqueous alcohol (to prepare the acetamidoximes), or with methanol in the presence of sodium methylate to prepare the corresponding imidate followed by reaction of the imidate intermediate with aqueous ammonium carbonate.
In preparing the acetamidoximes, the reaction proceeds when the substituted phenylthioacetonitrile and hydroxylamine are contacted and mixed in the presence of a base such as sodium carbonate, and an inert liquid reaction medium such as aqueous ethanol. The reaction proceeds at temperatures from about 50.degree. C. to about 75.degree. C. and is preferably carried out at temperatures of from about 65.degree. to about 70.degree. C. The exact proportions of the reactants to be employed can be varied, however, the reaction consumes the reactants in equimolar proportions and the use of the reactants in such proportions, or with a slight excess of the hydroxylamine reactant, is preferred. Greater than two fold molar excesses of hydroxylamine is neither necessary nor desirable. The reaction is generally complete in about six to twelve hours, depending on the temperature employed. The product can be separated by evaporation of the reaction medium under reduced pressure, taking up the residue in water and aqueous acid to neutralize remaining base, washing with organic solvents, and adding base to make the mixture alkaline. The amidoxime separates as a solid or an oil which solidifies on treatment by conventional techniques such as cooling, trituration, scratching, etc. The solid product can be purified by recrystallization from water alcohols or the like. Alternatively, the product can be converted to a pharmaceutically-acceptable salt and purified as the salt.
The acetamidines of the invention are conveniently prepared by a two-step process illustrated below: ##SPC2##
in the above formulae, the moiety R has the significance first set out above.
The first step proceeds when the substituted phenylthioacetonitrile is intimately mixed with methanol and a catalytic amount of sodium methylate. The reaction proceeds at temperatures of from about 0.degree. C. to 70.degree. C., and is conveniently carried out at room temperature. After the reaction mixture has been held for a period sufficient for the production of sufficient amount of the imidate intermediate (generally from about 3 to about 12 hours), an ammonium salt is added to the mixture and the mixture is maintained at a temperature within the same reaction temperature range until the second step is substantially complete, generally about 12 to 24 hours at room temperature. The product can be separated by evaporation of the reaction medium, and is obtained as the salt with the anion furnished by the ammonium salt reactant. Ammonium chloride is a preferred ammonium salt reactant, although ammonium salts with other pharmaceutically-acceptable anions can also be employed to produce other salts, such as the hydrobromide, sulfate, carbonate, etc. The product can be purified by conventional techniques such as washing and recrystallization from water, alcohols, dioxane and alcohols, and the like. Alternatively, it can be converted to the free base.
The pharmaceutically-acceptable salts of the free base substituted amidines can be prepared by dissolving the free base in a minimal amount of alcohol or ether and adding an alcohol solution of an acid such as hydrochloric acid, hydrobromic acid, malic acid, maleic acid or succinic acid until precipitation of the corresponding salt is complete. The salt can further be purified by recrystallization or converted to the free base form.
The free base substituted amidine can be prepared by hydrolysis of the salt in aqueous base. The salt is mixed with a molar equivalent amount of sodium hydroxide in aqueous solution, excess aqueous sodium carbonate or the like, after which the free base can be separated by extraction with an organic solvent. The solvent can be removed by conventional methods such as evaporation or distillation. The product can be purified by conventional procedures such as washing or recrystallization.